Anti-MiR122 Therapeutic Stuns HCV World with Single-Dose Efficacy Results

This morning, Regulus Therapeutics greeted us with amazing results from a phase I study of RG-101, an anti-microRNA 122 oligo for the treatment of HCV infection.  The results show that in the exploratory HCV-infected patient subgroup, a single dose of 2mg/kg of RG-101 resulted in a mean viral load reduction of 4.1log on day 29.  All responded with viral declines, with 6 and 3 of the 14 patients with viral levels below the level of quantitation on days 29 and 57, respectively.   

These results even exceed my own wildest imaginations (as discussed here yesterday) and I’m amazed how much this virus, in all patients, seems to have come to rely on this host-derived microRNA for replication and/or genome stabilization.

It is not clear whether increasing the dose to 4mg/kg, the pre-planned upper dose in the HCV-infected cohort for which dosing is ongoing will bring any additional benefit given that the biomarker data (host genes targeted by miR-122) from the healthy volunteers showed a plateau already at 2mg/kg, indicating the power of this GalNAc chemistry approach.  My guess is that the main benefit from a higher dose would be a decrease in response variability.

Interestingly, IL-28 status, frequently a predictor of treatment success, did not influence the results, nor did HCV genotype seem to have an impact (small numbers).  This further supports that RG-101 could fill some of the more attractive opportunities in the current HCV market.   

Regarding safety, mild and transient injection site reactions seemed most significant with no serious adverse events in the entire study, including the healthy volunteer cohorts (up to 8mg/kg).  This is also consistent with data for Alnylam’sALN-TTRsc which uses a similar GalNAc chemistry and where multiple doses up to 10mg/kg had been tolerated, with injection site reactions, especially at 10mg/kg, being the main safety finding.   

So what’s it all worth?  The results position RG-101 to facilitate a 4-week HCV dosing regimen (compared to typically 8-12 weeks currently), potentially in combination with a single direct-acting antiviral such as Olysio by Johnson&Johnson.  One or two injections maximum.  Great compliance, potentially pan-genotypic, ideal for the busy practicing physician who does not have the time nor inclination to know the ins and outs of each DAA.

In dollar terms, I’d like to think that with this drug profile, this overlooked compound and company are worth as much as what Merck recently paid for HCV drug developer Idenix: $3.85B. The market valuation of Regulus before the news: $300M.  Needlessly to say that I'm long the stock.

PS: GSK once had rights to a precursor compound of RG-101 which it did not exercise.  Importantly, at the time, Regulus’ anti-miR122 compound was not GalNAc-enabled.  This would have necessitated much more frequent dosing and higher dosages and resulted in less potent and more protracted viral declines, i.e. something that would not have been competitive in the current HCV marketplace.  But as often the case with Big Pharma and cutting-edge technology, today’s data clearly shows them wrong.  It has to be said though that GSK more or less got out of HCV which also would have explained GSK’s decision RE anti-miR122.

PPS: Congrats to Peter Sarnow and Catherine Jopling who in 2005 made the mind-boggling discovery that HCV relies on a microRNA for its replication.  I hope they will be handsomely rewarded for it.

Anti-miR122 Antagomir Successful in Fighting HCV in Chimpanzees

I just wanted to post this video by KENS 5 on the anti-miR122 studies in HCV-infected chimpanzees by Danish LNA company Santaris and researchers from the San Antonio Southwest Foundation for Biomedical Research. The study, just published online in Science, shows surprisingly potent reduction of HCV levels (2 1/2 logs) with an miR-122 antisense inhibitor and, at least equally important, without the emergence of viral escape mutants. While this study only involved four chimpanzees and human studies are still in the early phases (phase I, healthy volunteers), these results justify hopes that such a first-in-class agent could be a valuable component of future combination therapies with increased cure-rates, shortened treatment times, and maybe without the need for current standard-of-care component ribavirin.

Curiously in light of these promising results, it appears as if GSK let an option to the Santaris compound expire. While Big Pharma may have multiple reasons why it does not want to pursue a certain compound aside from the science (e.g. the fact that HDL-cholesterol was lowered as a result of miR-122 inhibition could warrant caution), for example product portfolio considerations, one possibility is that IP concerns and GSK's relationship with Regulus were important factors: Regulus has an exclusive license to the IP surrounding the fundamental work by Jopling and Sarnow on the role of miR-122 in HCV replication. While this may be good news for Regulus, I was made aware that the broad Esau and Tuschl patent applications on microRNAs as therapeutic targets and held by Regulus are being narrowed down considerably by the patent offices.

Note: For a more detailed discussion of this paper, please read the review by Mark Kay and myself in Molecular Therapy (click here).

Regulus Rx, Where One and One Equals Five

One has to be impressed by the way John Maraganore, chief astronomer and CEO of Alnylam, and his team are maximising the value of their company’s scientific know-how and intellectual property. Last week’s launch of Regulus Therapeutics, a joint venture with ISIS Pharmaceuticals focussed on the development of microRNA-based therapeutics, is the latest in a string of strategic decisions that positions Alnylam to lead and participate in the very promising field of RNAi-related therapies while wisely managing the company’s resources and respecting the scientific challenges ahead. The scientific and financial results speak for themselves and are starting to catch the attention and respect of Wall Street and beyond.

Forming this joint venture not only consolidates and complements much of the IP in microRNA-based therapeutics, it also allows the respective companies to focus on their core operations in RNAi and antisense while giving the new company a distinct identity and independence that should incentivise their employees and help attract 3rd party funding, particularly in the form of alliances with larger partners. The joint venture also acknowledges the fact that microRNA therapeutics sets a new paradigm for treating disease with its unique set of challenges and risks.

Based on pioneering work by Regulus SAB member David Bartel and his group at the MIT, it is now believed that the approximately 1000 human microRNAs regulate around one third of our genes, “that is one third of our genes” (Stanley Crooke). It follows that each microRNA targets multiple genes. Targeting a microRNA for therapy is therefore based on the premise that the functions of these genes are linked to a common biological process hence limiting the potential for unwanted side-effects by disturbing unrelated pathways. In this sense, microRNA- and RNAi-based therapies are opposite philosophies where siRNAs seek to surgically target single disease-associated genes, whereas microRNAs are aimed at whole networks. Genetic research supports both approaches, and a number of microRNAs have been shown in animal models and human cells to specifically affect discrete regulatory pathways, a fact that is arguably best understood by two key SAB members of Regulus Rx, namely David Bartel and David Baltimore. A recent catalogue of microRNAs established by yet another Regulus SAB member, Thomas Tuschl from the Rockefeller, however, suggests that many microRNAs are constitutively expressed in a number of tissues, thereby slightly questioning whether this is the case for most microRNAs. Although a truly exploding field of research, compared to RNAi Therapeutics where there are already an abundance of well-defined targets, the development of Regulus Rx will heavily depend on progress made in elucidating the exact role of specific microRNAs.

Regulus Rx’s first development program, targeting miR-122 for the treatment of Hepatitis C Virus (HCV) infection is a particularly interesting case. This program has been licensed from Stanford University where Catherine Jopling from Peter Sarnow’s group has shown that miR-122 specifically interacts with part of the HCV genome and thereby stimulates HCV replication. MiR-122 is by far the most abundant microRNA in the liver, and it is surprising that no obvious toxicities have been associated with its inhibition in vitro or in vivo, as demonstrated by work from both Alnylam and ISIS scientists. It is even thought that inhibiting it may have applications in managing cardiovascular disease. Earlier this year, Alnylam and ISIS were issued a patent covering miR-122 as a therapeutic target. I am quite curious to learn whether last week’s announcement of HCV miR-122 as the first development program of Regulus is also based on results targeting HCV replication by miR-122 inhibition in vivo. In this regard, it is notable that a leading group in HCV biology, the Rice group at Rockefeller only recently confirmed miR-122’s importance in HCV replication in a paper jointly published with Thomas Tuschl from the same institute.

Regulus Rx will be based in Carlsbad, CA, not only because of the better weather, but also because this is where ISIS Pharmaceuticals is located. This acknowledges the fact that antisense technology, pioneered and long dominated by ISIS, is the key enabling technology for antagonising mature microRNAs many of which are processed out of introns of RNA Polymerase II transcripts and therefore not a target for RNAi. This underscores the importance Alnylam has attributed to ISIS’ patent estate, also demonstrated by their exclusive licensing ISIS’ oligonucleotides modification patents for the use in double-stranded RNAi Therapeutics. It also sends out the subtle message that as Alnylam respects other parties’ IP it expects anybody interested in RNAi Therapeutics to follow this example by licensing from Alnylam.

The 50:50 joint venture also speaks volumes to the negotiating leverage Alnylam has gained in recent years, made possible in large part by its solid financial position. Only 3 months ago, the financial strength of Alnylam has allowed it to revise a partnership agreement with Medtronic that has given Alnylam a larger stake in the financial success of any drugs coming out of that collaboration in return for increased funding by Alnylam. Unlike ISIS which not long ago had to repeatedly issue debt to fund their operations and is biting its nails to gain financial freedom by partnering its ApoB100 antisense program, Alnylam could easily pay the $10M to equal the companies’ stake in the new venture. In addition to its financial muscle and Tuschl III which gives Regulus exclusive access to some of the most important microRNA targets, Alnylam further brings to the table its invaluable access to leading scientists in academia and Big Pharma alike.

Finally, it is notable that the otherwise wide-ranging technology access licenses that Alnylam has granted Novartis and Roche did not include microRNAs. It would therefore be appropriate that following last week’s development the newco be put on a solid financial footing through a significant partnership. But let’s give them some time for this as although the day may never end on Alnylam, on earth their day still has only 24 hours.

(For more on the scientific rationale for microRNA therapeutics, please read my Blog from 26 May, 2007: “MicroRNAs as Therapeutic Targets”)


PS: Once the dust has settled, we should learn more about the exact scope of Regulus Rx. Specifically, it is not clear to me yet whether in addition to antagonising microRNAs by antisense, the scope of Regulus will encompass the microRNA agonist approach as well where microRNAs mimics are introduced for therapeutic purposes. While this would strengthen Regulus’ portfolio, it would be a significant contribution of Alnylam IP since such mimics would essentially be based on siRNA technology.